Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

While previous studies have examined the association between vancomycin (VAN) exposure and MIC with regard to outcomes in methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B), none have explored if a relationship exists with the VAN minimum bactericidal concentration (MBC). The objective of this study was to evaluate the VAN 24-h area under the curve (AUC24)/MBC ratio as a pharmacodynamic predictor of mortality. This retrospective cohort study included patients treated with VAN for MRSA-B with the primary outcome of 30-day all-cause mortality. Data collected included patient demographics, comorbidities, antimicrobial treatment data, therapeutic drug levels, and laboratory and microbiological data. Vancomycin MICs and MBCs were determined by Etest (MIC only) and broth microdilution (BMD). The vancomycin AUC24 was determined by pharmacokinetic maximum a posteriori probability Bayesian (MAP-Bayesian) analysis. The most significant breakpoint for 30-day mortality was determined by classification and regression tree (CART) analysis. The association between pharmacodynamic parameters (VAN AUC24/MICBMD, VAN AUC24/MICEtest, and AUC24/MBCBMD) and mortality were determined by χ2 and multivariable Poisson regression. Overall mortality in this cohort (n = 53) was 20.8% (n = 11/53), and all corresponding MRSA blood isolates were VAN susceptible (MIC range, 0.5 to 2 μg/ml; MIC50, 1 μg/ml; MIC90, 1 μg/ml). The CART-derived breakpoints for mortality were 176 (VAN AUC24/MBC) and 334 (VAN AUC24/MICBMD). In multivariable analysis, the association between a VAN AUC24/MBC of ≥176 and survival persisted, but VAN AUC24/MICBMD values (≥334 or ≥400) were not associated with improved mortality. In conclusion, VAN AUC24/MBC was a more important predictor of 30-day mortality than VAN AUC24/MIC for MRSA-B

Effect of Duplicate Isolates of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus on Antibiogram Data

This is the published version, also available here: http://www.dx.doi.org/10.1128/JCM.41.10.4611-4616.2003

Nationwide antibiogram analysis using NCCLS M39-A guidelines

This is the published version, also available here: http://dx.doi.org/10.1128/JCM.43.6.2629-2634.2005.Lack of standardization in antibiogram (ABGM) preparation (the overall profile of antimicrobial susceptibility results of a microbial species to a battery of antimicrobial agents) has not been addressed until recently. The objective of this study was to analyze current antibiograms using the recently published NCCLS M39-A guidelines for preparation of antibiograms to identify areas for improvement in the reporting of antibiogram susceptibility data. Antibiograms from across the United States were obtained by various methods, including direct mailings, Internet searches, and professional contacts. Each ABGM collected was analyzed using prospectively defined elements from the M39-A guidelines. Additionally, seven quality indicators were also evaluated to look for the reporting of any atypical or inappropriate susceptibility data. The 209 antibiograms collected from 149 institutions showed at least 85% compliance to 5 of the 10 M39-A elements analyzed. Clinically relevant elements not met included annual analysis, duplicate isolate notation, and the exclusion of organisms with fewer than 10 isolates. As for the quality indicators evaluated, unexpected results included the 7% of antibiograms that reported 0% ampicillin susceptibility for Klebsiella pneumoniae. These findings suggest that antibiograms should be reviewed thoroughly by infectious disease specialists (physicians and pharmacists), clinical microbiologists, and infection control personnel for identification of abnormal findings prior to distribution

Differential activation of inflammatory pathways in A549 type II pneumocytes by Streptococcus pneumoniae strains with different adherence properties

BACKGROUND: Adherence of Streptococcus pneumoniae bacteria to lung cells is a first step in the progression from asymptomatic carriage to pneumonia. Adherence abilities vary widely among S. pneumoniae patient isolates. In this study, the binding properties of S. pneumoniae isolates and the effects of binding on activation of the Nuclear Factor-Kappa-B (NFκB) pathway and cytokine secretion by type II pneumocytes were measured. METHODS: Mechanisms of high- and low-binding S. pneumoniae adherence to A549 cells were investigated by blocking putative receptors on bacteria and host cells with antibody and by eluting choline-binding proteins off of bacterial surfaces. NFκB activation was measured by western blot and immunocytochemistry and cytokine secretion was detected by a protein array. RESULTS: This study shows that S. pneumoniae isolates from pneumonia patients (n = 298) can vary by as much as 1000-fold in their ability to bind to human lung epithelial cells. This difference resulted in differential activation of the NFκB pathway. High-, but not low-binding S. pneumoniae used Choline-binding protein A (CbpA) to bind to complement component C3 on epithelial cell surfaces. Interleukin-8 (IL-8) was the only cytokine secreted by cells treated with either low- or high-binding S. pneumoniae. CONCLUSION: These results indicate that S. pneumoniae clinical isolates are not homogeneous in their interaction with host epithelial cells. The differential activation of host cells by high- and low-binding S. pneumoniae strains could have implications for the treatment of pneumococcal pneumonia and for vaccine development

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effect of Duplicate Isolates of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus on Antibiogram Data

Duplicate Staphylococcus aureus isolates were analyzed to determine the impact of multiple isolates from the same patient on annual antibiogram data. During a 6-year period (1996 to 2001), 3,227 patients with 4,844 S. aureus isolates were evaluated. A total of 39% of patients with methicillin-resistant S. aureus (MRSA) (n = 860) and 23% of patients with methicillin-susceptible S. aureus (MSSA) (n = 2,367) infections had duplicate isolates. Cumulative data show that 91% of the patients during this 6-year period with duplicate isolates (2 to 13 duplicates/year) did not switch between MSSA and MRSA but retained the original S. aureus strain whether it was MSSA or MRSA. Rates of MRSA were calculated for each year by using all isolates and then eliminating duplicates. The impact of duplicate MRSA and MSSA isolates was evaluated by using the ratio of isolates per patient such that ratios of >1.0 indicate >1 isolate per patient. The 6-year ratio for MRSA was 1.90 isolates/patient, and the ratio for MSSA was 1.35. A significant difference (P < 0.05) was noted in the MRSA rates in 4 of 6 years when duplicate isolates were removed. Common phenotypic antibiogram patterns were compared for all MRSA isolates during the 6-year period, and 64% were of a single antibiogram phenotype. Eighty-eight percent of patients with duplicate MRSA isolates had phenotypically identical multiple isolates. The rate of MRSA differs when duplicate isolates are removed from the antibiogram data

Nationwide Antibiogram Analysis Using NCCLS M39-A Guidelines

Lack of standardization in antibiogram (ABGM) preparation (the overall profile of antimicrobial susceptibility results of a microbial species to a battery of antimicrobial agents) has not been addressed until recently. The objective of this study was to analyze current antibiograms using the recently published NCCLS M39-A guidelines for preparation of antibiograms to identify areas for improvement in the reporting of antibiogram susceptibility data. Antibiograms from across the United States were obtained by various methods, including direct mailings, Internet searches, and professional contacts. Each ABGM collected was analyzed using prospectively defined elements from the M39-A guidelines. Additionally, seven quality indicators were also evaluated to look for the reporting of any atypical or inappropriate susceptibility data. The 209 antibiograms collected from 149 institutions showed at least 85% compliance to 5 of the 10 M39-A elements analyzed. Clinically relevant elements not met included annual analysis, duplicate isolate notation, and the exclusion of organisms with fewer than 10 isolates. As for the quality indicators evaluated, unexpected results included the 7% of antibiograms that reported <100% vancomycin susceptibility for Staphylococcus aureus, 24% that had inconsistent beta-lactam susceptibility for Staphylococcus aureus, 20% that reported <100% imipenem susceptibility for Escherichia coli, and 37% that reported >0% ampicillin susceptibility for Klebsiella pneumoniae. These findings suggest that antibiograms should be reviewed thoroughly by infectious disease specialists (physicians and pharmacists), clinical microbiologists, and infection control personnel for identification of abnormal findings prior to distribution

Coactivating Signals for the Hepatic Lymphocyte Gamma Interferon Response to Francisella tularensis

The facultative intracellular bacterium Francisella tularensis is capable of causing systemic infections in various hosts, including mice and humans. The liver is a major secondary site of F. tularensis infection, but hepatic immune responses to the pathogen remain poorly defined. Immune protection against the pathogen is thought to depend on the cytokine gamma interferon (IFN-γ), but the cellular basis for this response has not been characterized. Here we report that natural killer cells from the livers of naïve uninfected mice produced IFN-γ when challenged with live bacteria in vitro and that the responses were greatly increased by coactivation of the cells with either recombinant interleukin-12 (IL-12) or IL-18. Moreover, the two cytokines had strong synergistic effects on IFN-γ induction. Neutralizing antibodies to either IL-12 or IL-18 inhibited IFN-γ production in vitro, and mice deficient in the p35 subunit of IL-12 failed to show IFN-γ responses to bacterial challenge either in vitro or in vivo. Clinical isolates of highly virulent type A Francisella tularensis subsp. tularensis organisms were comparable to the live attenuated vaccine strain of Francisella tularensis subsp. holarctica in their ability to induce IL-12 and IFN-γ expression. These findings demonstrate that cells capable of mounting IFN-γ responses to F. tularensis are resident within the livers of uninfected mice and depend on coactivation by IL-12 and IL-18 for optimum responses