Duodenal mucosa of untreated celiac disease patients has altered expression of the GAS6 and PROS1 and the negative regulator tyrosine kinase TAM receptors subfamily.

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.

Factors associated with Mediterranean diet adherence in a sample of high socio-economic status children from southern Spain.

OBJECTIVE: The present study examined the association of BMI, fat mass, physical activity engagement (PA), maximal oxygen consumption (VO2max), screen time and academic performance (AP) with Mediterranean diet (MD) adherence in a sample of high socio-economic status (SES) children. DESIGN: A non-randomised design was used. A multilinear regression model was developed using backward elimination. Analysis included variables pertaining to age, BMI, VO2max, fat percentage, AP, PA engagement and screen time. All participants had a high SES and so this variable was not included as a predictor. Data met the assumptions required for multiple regressions in terms of linearity, homoscedasticity, normality, independence and non-multicollinearity. SETTING: Two state and three mixed funding schools in Granada, Spain. PARTICIPANTS: Data were collected from 244 children aged between 10 and 12 years. RESULTS: Better AP, higher PA engagement and lower screen time were found to be predictive of MD adherence. These variables explained 22·9 % of the variance in data measuring adolescent MD adherence. CONCLUSIONS: The present study suggests that, in addition to SES, PA, AP and screen time are important components to consider when targeting improvements in MD adherence in children. It is, therefore, concluded that interventions targeting improvements in PA, AP and screen time are needed to promote MD adherence in children, regardless of SES.

Coexistence of apoptosis, pyroptosis, and necroptosis pathways in celiac disease.

Usually, the massive elimination of cells under steady-state conditions occurs by apoptosis, which is also acknowledged to explain the loss of enterocytes in the small intestine of celiac disease (CD) patients. However, little is known about the role of proinflammatory cell death pathways in CD. Here, we have used confocal microscopy, western blot, and RT-qPCR analysis to assess the presence of regulated cell death pathways in the duodenum of CD patients. We found an increased number of dead (TUNEL+) cells in the lamina propria of small intestine of CD patients, most of them are plasma cells (CD138+). Many dying cells expressed FAS and were in close contact with CD3+ T cells. Caspase-8 and caspase-3 expression was increased in CD, confirming the activation of apoptosis. In parallel, caspase-1, IL-1ß, and GSDMD were increased in CD samples indicating the presence of inflammasome-dependent pyroptosis. Necroptosis was also present, as shown by the increase of RIPK3 and phosphorylate MLKL. Analysis of published databases confirmed that CD has an increased expression of regulated cell death -related genes. Together, these results reveal that CD is characterized by cell death of different kinds. In particular, the presence of proinflammatory cell death pathways may contribute to mucosal damage.

Expanding the definition beyond surveillance criteria reveals a large burden of osteomyelitis caused by group B Streptococcus in the United States Veterans Health Administration.

BACKGROUND: Population-based surveillance studies may underestimate osteomyelitis caused by Group B Streptococcus (GBS). We analyzed cases of GBS osteomyelitis, including patients diagnosed using an expanded case definition that incorporates cultures from non-sterile sites, as well as cultures from normally sterile sites. METHODS: We retrospectively examined a cohort of veterans with the diagnosis of osteomyelitis between 2008 and 2017. Cases of definite GBS osteomyelitis required GBS isolation from normally sterile sites, (e.g., blood or bone). Cases of probable GBS osteomyelitis permitted GBS isolation from non-sterile sites (e.g., surgical sites, wounds). We compared comorbid conditions, lower extremity amputation and mortality rates in these groups. RESULTS: Among 1281 cases of GBS osteomyelitis, the median age was 63 years, 87% had diabetes mellitus and 37% had peripheral vascular disease. Similar characteristics were found in 768 (60%) cases classified as definite and 513 (40%) classified as probable GBS osteomyelitis. Polymicrobial infection was less frequent in patients with definite than with probable GBS osteomyelitis (45% vs. 85%; P < 0.001). Mortality rates within 1-year were similar for definite and probable GBS osteomyelitis (12% vs. 10%). Amputation within 1-year occurred in 21% of those with definite and 10% of those with probable GBS osteomyelitis of the lower extremity, with comparable rates in the subset with monomicrobial infection. CONCLUSIONS: Expanding the definition of GBS osteomyelitis to include cases with cultures from non-sterile sites may be warranted, increasing the estimated burden of GBS osteomyelitis. This can help guide preventive efforts to reduce the impact of GBS osteomyelitis.

Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT): A Framework for Assessing Antibiotic Selection Strategies in the Presence of Drug Resistance.

The complexities of antibiotic resistance mean that successful stewardship must consider both the effectiveness of a given antibiotic and the spectrum of that therapy to minimize imposing further selective pressure. To meet this challenge, we propose the Desirability of Outcome Ranking approach for the Management of Antimicrobial Therapy (DOOR MAT), a flexible quantitative framework that evaluates the desirability of antibiotic selection. Herein, we describe the steps required to implement DOOR MAT and present examples to illustrate how the desirability of treatment selection can be evaluated using resistance information. While treatments and the scoring of treatment selections must be adapted to specific clinical settings, the principle of DOOR MAT remains constant: The most desirable antibiotic choice effectively treats the patient while exerting minimal pressure on future resistance.

Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) Reveals Improvements in the Treatment of Bloodstream Infections Caused by Escherichia coli and Klebsiella pneumoniae in Patients from the Veterans Health Administration.

BACKGROUND: Reductions in the use of broad-spectrum antibiotics is a cornerstone of antimicrobial stewardship. We aim to demonstrate use of the Desirability of Outcome Ranking Approach for the Management of Antimicrobial Therapy (DOOR MAT) to evaluate the treatment of Escherichia coli and Klebsiella pneumoniae bloodstream infections in patients from the Veterans Health Administration (VHA) across a decade. METHODS: Using electronic records, we determined empiric and definitive antibiotic treatments, clinical characteristics, and 30-day mortality of patients with monomicrobial E. coli and K. pneumoniae bloodstream infections hospitalized in VHA medical centers from 2009 to 2018. Focusing on patients treated with parenteral ß-lactams and with available antibiotic susceptibility testing results, we applied a range of DOOR MAT scores that reflect the desirability of antibiotic choices according to spectrum and activity against individual isolates. We report trends in resistance and desirability of empiric and definitive antibiotic treatments. RESULTS: During the 10-year period analyzed, resistance to expanded-spectrum cephalosporins and fluoroquinolones increased in E. coli but not in K. pneumoniae, while resistance to carbapenems and piperacillin-tazobactam remained unchanged. In 6451 cases analyzed, we observed improvements in DOOR MAT scores consistent with deescalation. Improvement in desirability of definitive treatment compared with empiric treatment occurred in 26% of cases, increasing from 16% in 2009 to 34% in 2018. Reductions in overtreatment were sustained and without negative impact on survival. CONCLUSIONS: DOOR MAT provides a framework to assess antibiotic treatment of E. coli and K. pneumoniae bloodstream infections and can be a useful metric in antimicrobial stewardship.

Interplay between Meropenem and Human Serum Albumin on Expression of Carbapenem Resistance Genes and Natural Competence in Acinetobacter baumannii.

Acinetobacter baumannii A118, a carbapenem-susceptible strain, and AB5075, carbapenem resistant, were cultured in lysogeny broth (LB) or LB with different supplements, such as 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5% HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation in A. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus-associated genes. The combination meropenem plus 3.5% HSA produced a synergistic enhancement in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumannii AMA16 blaNDM-1 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may increase the stress response, the expression of genes involved in natural competence is increased in A. baumannii. This process may favor the acquisition of foreign DNA and accelerate evolution.

Programmed Cell Death in the Small Intestine: Implications for the Pathogenesis of Celiac Disease.

The small intestine has a high rate of cell turnover under homeostatic conditions, and this increases further in response to infection or damage. Epithelial cells mostly die by apoptosis, but recent studies indicate that this may also involve pro-inflammatory pathways of programmed cell death, such as pyroptosis and necroptosis. Celiac disease (CD), the most prevalent immune-based enteropathy, is caused by loss of oral tolerance to peptides derived from wheat, rye, and barley in genetically predisposed individuals. Although cytotoxic cells and gluten-specific CD4+ Th1 cells are the central players in the pathology, inflammatory pathways induced by cell death may participate in driving and sustaining the disease through the release of alarmins. In this review, we summarize the recent literature addressing the role of programmed cell death pathways in the small intestine, describing how these mechanisms may contribute to CD and discussing their potential implications.

Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based Regimens for the Treatment of Drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination that often retains activity against resistant Pseudomonas aeruginosa. The comparative safety and efficacy vs polymyxins or aminoglycosides in this setting remains unknown. METHODS: A retrospective, multicenter, observational cohort study was performed. Patients who received ceftolozane/tazobactam were compared with those treated with either polymyxin or aminoglycoside-based regimens for infections due to drug-resistant P. aeruginosa. Multivariate logistic regression was performed controlling for factors associated with treatment to assess the independent impact of ceftolozane/tazobactam on clinical cure, acute kidney injury (AKI), and in-hospital mortality. RESULTS: A total of 200 patients were included (100 in each treatment arm). The cohort represented an ill population with 69% in the intensive care unit, 63% mechanically ventilated, and 42% in severe sepsis or septic shock at infection onset. The most common infection type was ventilator-associated pneumonia (52%); 7% of patients were bacteremic. Combination therapy was more commonly used in polymyxin/aminoglycoside patients than those who received ceftolozane/tazobactam (72% vs 15%, P < .001). After adjusting for differences between groups, receipt of ceftolozane/tazobactam was independently associated with clinical cure (adjusted odds ratio [aOR], 2.63; 95% confidence interval [CI], 1.31-5.30) and protective against AKI (aOR, 0.08; 95% CI, 0.03-0.22). There was no difference in in-hospital mortality. The number needed to treat for a clinical cure with ceftolozane/tazobactam was 5, and the number needed to harm with AKI with a polymyxin/aminoglycoside was 4. CONCLUSIONS: These data support the preferential use of ceftolozane/tazobactam over polymyxins or aminoglycosides for drug-resistant P. aeruginosa infections.

Monitoring Ceftazidime-Avibactam and Aztreonam Concentrations in the Treatment of a Bloodstream Infection Caused by a Multidrug-Resistant Enterobacter sp. Carrying Both Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-ß-Lactamase-1.

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-ß-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.

Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial.

BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

Precision Medicine and Mysteries in Clinical Microbiology: Rationalizing Epidemiology, Genotype, and Phenotype To Guide Therapeutics.

Whole-genome sequencing (WGS) using MinION was used to characterize high-risk clones of Escherichia coli and Klebsiella pneumoniae harboring bla NDM-5, bla OXA-181, and bla CTX-M-15, as well as Pseudomonas aeruginosa harboring bla NDM, in a patient who received health care in India. Synergy testing demonstrated the activity of aztreonam and ceftazime-avibactam in combination. This case illustrates a "precision medicine" approach where deeper understanding of the genotype through WGS and of the phenotype through synergy testing formed the basis for rational combination therapy.

Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV.

BACKGROUND: Overcoming ß-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa. METHODS: In this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer ß-lactam/ß-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO). RESULTS: We found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA). CONCLUSIONS: The diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.

Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae.

Background: The efficacy of ceftazidime-avibactam-a cephalosporin-ß-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results: Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Conclusions: Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.

A virtual clinic improves pneumococcal vaccination coverage among patients living with HIV at a Veterans Affairs Medical Center.

People living with the human immunodeficiency virus (HIV) should receive pneumococcal vaccinations as part of their routine health maintenance. Our goal was to create a "virtual clinic" to help increase rates of pneumococcal vaccination among people living with HIV without adding substantially to the workload of primary providers. We used administrative data from our Veterans Affairs (VA) medical center to identify a cohort of veterans living with HIV who were not current with either the 13-valent pneumococcal conjugate vaccine (PCV13), the 23-valent pneumococcal polysaccharide vaccine (PPSV23) or both. We enrolled these individuals (n = 99) into a virtual clinic, notified providers via the electronic medical record and mailed letters to the veterans recommending they receive a pneumococcal vaccine. We also wrote orders for the appropriate pneumococcal vaccine that expired after 90 days. Among the virtual clinic cohort, 38% (38/99) of patients received the recommended vaccine within 180 days. Concurrent with our intervention, the Veterans Health Administration deployed a system-wide pneumococcal vaccine clinical reminder that incorporated recent PCV13 recommendations. To discern any effect of the virtual clinic beyond that of the clinical reminder, we compared the rate of PCV13 vaccinations among all HIV-positive veterans at our institution to the equivalent population from 2 other VA medical centers in Ohio. With consideration of the VHA's system-wide clinical reminder, the proportion of HIV-positive patients who received PCV13 in the first 90 days following the virtual clinic intervention was greater at our facility compared to another Ohio VA medical center (P < 0.05). The virtual clinic improved the pneumococcal vaccine coverage among HIV-positive veterans. These outcomes suggest that even in conjunction with a system-wide clinical reminder, the virtual clinic strategy improves vaccination rates among a high-risk population.

"Double carbapenem" and oral fosfomycin for the treatment of complicated urinary tract infections caused by blaNDM -harboring Enterobacteriaceae in kidney transplantation.

Infections with carbapenemase-producing carbapenem-resistant Enterobacteriaceae represent an emergent problem worldwide. Treatment of infections caused by New Delhi metallo-beta-lactamase (NDM)-harboring Enterobacteriaceae is particularly challenging as it frequently involves the use of nephrotoxic agents, which is problematic in kidney transplant recipients and non-renal transplant patients with marginal kidney function. We present two cases of urinary tract infections caused by NDM-harboring Enterobacteriaceae successfully treated with a combination of "double carbapenem" and oral fosfomycin.

Intestinal Carriage of Carbapenemase-Producing Organisms: Current Status of Surveillance Methods.

Carbapenemases have become a significant mechanism for broad-spectrum ß-lactam resistance in Enterobacteriaceae and other Gram-negative bacteria such as Pseudomonas and Acinetobacter spp. Intestinal carriage of carbapenemase-producing organisms (CPOs) is an important source of transmission. Isolation of carriers is one strategy that can be used to limit the spread of these bacteria. In this review, we critically examine the clinical performance, advantages, and disadvantages of methods available for the detection of intestinal carriage of CPOs. Culture-based methods (Centers for Disease Control and Prevention [CDC] protocols, chromogenic media, specialized agars, and double-disk synergy tests) for detecting carriage of CPOs are convenient due to their ready availability and low cost, but their limited sensitivity and long turnaround time may not always be optimal for infection control practices. Contemporary nucleic acid amplification techniques (NAATs) such as real-time PCR, hybridization assays, loop-mediated isothermal amplification (LAMP), or a combined culture and NAAT approach may provide fast results and/or added sensitivity and specificity compared with culture-based methods. Infection control practitioners and clinical microbiologists should be aware of the strengths and limitations of available methods to determine the most suitable approach for their medical facility to fit their infection control needs.

An Analysis of the Epidemic of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Convergence of Two Evolutionary Mechanisms Creates the "Perfect Storm".

Background: Carbapenem resistance is a critical healthcare challenge worldwide. Particularly concerning is the widespread dissemination of Klebsiella pneumoniae carbapenemase (KPC). Klebsiella pneumoniae harboring blaKPC (KPC-Kpn) is endemic in many areas including the United States, where the epidemic was primarily mediated by the clonal dissemination of Kpn ST258. We postulated that the spread of blaKPC in other regions occurs by different and more complex mechanisms. To test this, we investigated the evolution and dynamics of spread of KPC-Kpn in Colombia, where KPC became rapidly endemic after emerging in 2005. Methods: We sequenced the genomes of 133 clinical isolates recovered from 24 tertiary care hospitals located in 10 cities throughout Colombia, between 2002 (before the emergence of KPC-Kpn) and 2014. Phylogenetic reconstructions and evolutionary mapping were performed to determine temporal and genetic associations between the isolates. Results: Our results indicate that the start of the epidemic was driven by horizontal dissemination of mobile genetic elements carrying blaKPC-2, followed by the introduction and subsequent spread of clonal group 258 (CG258) isolates containing blaKPC-3. Conclusions: The combination of 2 evolutionary mechanisms of KPC-Kpn within a challenged health system of a developing country created the "perfect storm" for sustained endemicity of these multidrug-resistant organisms in Colombia.

A 17-Year Nationwide Study of Burkholderia cepacia Complex Bloodstream Infections Among Patients in the United States Veterans Health Administration.

Background: Burkholderia cepacia complex (Bcc) are a group of multidrug-resistant gram-negative bacteria rarely reported in patients without cystic fibrosis (CF) or immunocompromising conditions. We investigated Bcc bloodstream infections (BSIs) in a cohort of non-CF patients from the US Veterans Health Administration (VHA). Methods: Using VHA databases, we identified patients with Bcc BSI at facilities nationwide from 1999 through 2015. We ascertained clinical characteristics, treatments, and outcomes and identified factors associated with 30-day mortality in logistic regression analysis. Results: We identified 248 patients with Bcc BSI, who were of advanced age (mean, 68 years), chronically ill, and had severe disease. The most common sources were central venous catheters (41%) and pneumonia (20%). Most cases were hospital-acquired (155 [62%]) or healthcare-associated (70 [28%]). Mortality at 14, 30, and 90 days was 16%, 25%, and 36%, respectively. Trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones were active against 94% and 88% of isolates, respectively. Susceptibility to ceftazidime and meropenem occurred in approximately 70% of the isolates. The most prescribed antibiotics were fluoroquinolones (35%), followed by carbapenems (20%), TMP-SMX (18.5%), and ceftazidime (11%). In regression analysis, age (OR, 1.06 [95% confidence interval {CI}, 1.02-1.10], per added year) and the Pitt bacteremia score (OR, 1.65 [95% CI, 1.44-1.94], per unit increase) were associated with higher 30-day mortality. Conclusions: In this large cohort of BSIs caused by Bcc, cases were mostly hospital-acquired and we observed high mortality, significant resistance to ceftazidime, and limited use of TMP-SMX. These observations add to our understanding of Bcc infection in non-CF patients and highlight the need for interventions to improve their outcome.