Antimicrobial Stewardship Programs

Antimicrobial Stewardship Programs (ASPs) are becoming increasingly prevalent in the United States as concerns continue to mount regarding antimicrobial resistance and the lack of new, novel antibiotics being introduced. There are a multitude of factors that have contributed to the escalation in antimicrobial resistance, with some of the more common concerns being overly broad antimicrobial coverage and prolonged antimicrobial treatment amongst others. While antimicrobial resistance is a problem of international proportion, each health care institution remains responsible for assessing its own protocols pertinent to antimicrobial usage. ASPs have had unparalleled success in achieving their goals due to the collaboration of health care personnel, informatics, data collection, and effective policies being employed. While the pharmaceutical industry struggles with the development of novel antimicrobials, ASPs are a critical component to promote the continued efficacy of currently available antimicrobials. A considerable number of strategies have been established to implement and manage an effective institutional ASP, including educational programs, the development of institutional antimicrobial and disease state guidelines, prior approval for certain broad-spectrum agents, post-prescription review, and computer-based decision support. However, resources are often limited thus creating barriers for institutional ASP success. Some common barriers include a lack of fundraising, inadequate or absent diagnostic facilities, poor data collection, variation in data collection, a lack of communication among various health care professionals and a lack of cooperation among health care facilities. ASPs have the potential to reduce antimicrobial resistance evolution and therefore improve patient outcomes. The involvement of multiple health care professionals, including pharmacists, is imperative to the success of an ASP

Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections

This article provides a comprehensive review of currently available treatment options for infections due to carbapenem-resistant Enterobacteriaceae (CRE). Antimicrobial resistance in Gram-negative bacteria is an emerging and serious global public health threat. Carbapenems have been used as the “last-line” treatment for infections caused by resistant Enterobacteriaceae, including those producing extended spectrum ß-lactamases. However, Enterobacteriaceae that produce carbapenemases, which are enzymes that deactivate carbapenems and most other ß-lactam antibiotics, have emerged and are increasingly being reported worldwide. Despite this increasing burden, the most optimal treatment for CRE infections is largely unknown. For the few remaining available treatment options, there are limited efficacy data to support their role in therapy. Nevertheless, current treatment options include the use of older agents, such as polymyxins, fosfomycin, and aminoglycosides, which have been rarely used due to efficacy and/or toxicity concerns. Optimization of dosing regimens and combination therapy are additional treatment strategies being explored. Carbapenem-resistant Enterobacteriaceae infections are associated with poor outcomes and high mortality. Continued research is critically needed to determine the most appropriate treatment

Pixel-Based Absorption Correction for Dual-Tracer Fluorescence Imaging of Receptor Binding Potential

Ratiometric approaches to quantifying molecular concentrations have been used for decades in microscopy, but have rarely been exploited in vivo until recently. One dual-tracer approach can utilize an untargeted reference tracer to account for non-specific uptake of a receptor-targeted tracer, and ultimately estimate receptor binding potential quantitatively. However, interpretation of the relative dynamic distribution kinetics is confounded by differences in local tissue absorption at the wavelengths used for each tracer. This study simulated the influence of absorption on fluorescence emission intensity and depth sensitivity at typical near-infrared fluorophore wavelength bands near 700 and 800 nm in mouse skin in order to correct for these tissue optical differences in signal detection. Changes in blood volume [1-3%] and hemoglobin oxygen saturation [0-100%] were demonstrated to introduce substantial distortions to receptor binding estimates (error \u3e 30%), whereas sampled depth was relatively insensitive to wavelength (error \u3c 6%). In response, a pixel-by-pixel normalization of tracer inputs immediately post-injection was found to account for spatial heterogeneities in local absorption properties. Application of the pixel-based normalization method to an in vivo imaging study demonstrated significant improvement, as compared with a reference tissue normalization approach

Signal Intensity Analysis and Optimization for in Vivo Imaging of Cherenkov and Excited Luminescence.

During external beam radiotherapy (EBRT), in vivo Cherenkov optical emissions can be used as a dosimetry tool or to excite luminescence, termed Cherenkov-excited luminescence (CEL) with microsecond-level time-gated cameras. The goal of this work was to develop a complete theoretical foundation for the detectable signal strength, in order to provide guidance on optimization of the limits of detection and how to optimize near real time imaging. The key parameters affecting photon production, propagation and detection were considered and experimental validation with both tissue phantoms and a murine model are shown. Both the theoretical analysis and experimental data indicate that the detection level is near a single photon-per-pixel for the detection geometry and frame rates commonly used, with the strongest factor being the signal decrease with the square of distance from tissue to camera. Experimental data demonstrates how the SNR improves with increasing integration time, but only up to the point where the dominance of camera read noise is overcome by stray photon noise that cannot be suppressed. For the current camera in a fixed geometry, the signal to background ratio limits the detection of light signals, and the observed in vivo Cherenkov emission is on the order of 100×  stronger than CEL signals. As a result, imaging signals from depths  \u3c 15 mm is reasonable for Cherenkov light, and depths  \u3c 3 mm is reasonable for CEL imaging. The current investigation modeled Cherenkov and CEL imaging of two oxygen sensing phosphorescent compounds, but the modularity of the code allows for easy comparison of different agents or alternative cameras, geometries or tissues

Improved Tumor Contrast Achieved by Single Time Point Dual-Reporter Fluorescence Imaging

In this study, we demonstrate a method to quantify biomarker expression that uses an exogenous dual-reporter imaging approach to improve tumor signal detection. The uptake of two fluorophores, one nonspecific and one targeted to the epidermal growth factor receptor (EGFR), were imaged at 1 h in three types of xenograft tumors spanning a range of EGFR expression levels (n  =  6 in each group). Using this dual-reporter imaging methodology, tumor contrast-to-noise ratio was amplified by \u3e6 times at 1 h postinjection and \u3e2 times at 24 h. Furthermore, by as early as 20 min postinjection, the dual-reporter imaging signal in the tumor correlated significantly with a validated marker of receptor density (P  \u3c  0.05, r  =  0.93). Dual-reporter imaging can improve sensitivity and specificity over conventional fluorescence imaging in applications such as fluorescence-guided surgery and directly approximates the receptor status of the tumor, a measure that could be used to inform choices of biological therapies

The Impact of Multidrug-Resistant Organisms on Outcomes in Patients with Diabetic Foot Infections

Background. Multidrug-resistant organisms (MDROs) are important diabetic foot infection (DFI) pathogens. This study evaluated the impact of DFIs associated with MDRO pathogens (DFI-MDRO) on clinical outcomes. Methods. Adults admitted to Detroit Medical Center from January 2012 to December 2015 with culture-positive DFI were included. Associations between outcomes and DFI-MDRO (evaluated as a single group that included methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci, Enterobacteriaceae resistant to third-generation cephalosporin [3GCR-EC], Acinetobacter baumannii, and Pseudomonas aeruginosa) were analyzed. Outcomes included above- and below-knee lower extremity amputation (LEA), readmissions, and mortality within a year after DFI. A propensity score predicting the likelihood of having DFI-MDRO was computed by comparing patients with DFI-MDRO with patients with DFI with non-MDRO pathogens (DFI-non-MDRO). Using conditional logistic regression, DFI-MDRO was analyzed as an independent variable after patients in the MDRO and non-MDRO groups were matched by propensity score. Results. Six hundred forty-eight patients were included, with a mean age ± SD of 58.4 ± 13.7. Most patients in the cohort presented with chronic infection (75%). DFI-MDRO occurred in greater than one-half of the cohort (n = 364, 56%), and MRSA was the most common MDRO (n = 224, 62% of the DFI-MDRO group). In propensity-matched analyses, DFI-MDRO was not associated with 1-year LEA or readmissions, but was associated with recurrent DFI episodes (odds ratio, 2.1; 95% confidence interval, 1.38–3.21). Conclusions. DFI-MDRO was associated with a 2-fold increased risk of recurrent DFI compared with patients with DFI-non-MDRO

Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer.

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics

Dual-Tracer Background Subtraction Approach for Fluorescent Molecular Tomography

Diffuse fluorescence tomography requires high contrast-to-background ratios to accurately reconstruct inclusions of interest. This is a problem when imaging the uptake of fluorescently labeled molecularly targeted tracers in tissue, which can result in high levels of heterogeneously distributed background uptake. We present a dual-tracer background subtraction approach, wherein signal from the uptake of an untargeted tracer is subtracted from targeted tracer signal prior to image reconstruction, resulting in maps of targeted tracer binding. The approach is demonstrated in simulations, a phantom study, and in a mouse glioma imaging study, demonstrating substantial improvement over conventional and homogenous background subtraction image reconstruction approaches

Dynamic Dual-Tracer MRI-Guided Fluorescence Tomography to Quantify Receptor Density In Vivo

The up-regulation of cell surface receptors has become a central focus in personalized cancer treatment; however, because of the complex nature of contrast agent pharmacokinetics in tumor tissue, methods to quantify receptor binding in vivo remain elusive. Here, we present a dual-tracer optical technique for noninvasive estimation of specific receptor binding in cancer. A multispectral MRI-coupled fluorescence molecular tomography system was used to image the uptake kinetics of two fluorescent tracers injected simultaneously, one tracer targeted to the receptor of interest and the other tracer a nontargeted reference. These dynamic tracer data were then fit to a dual-tracer compartmental model to estimate the density of receptors available for binding in the tissue. Applying this approach to mice with deep-seated gliomas that overexpress the EGF receptor produced an estimate of available receptor density of 2.3 ± 0.5 nM (n = 5), consistent with values estimated in comparative invasive imaging and ex vivo studies

In Vitro Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae

ABSTRACT The multidrug resistance profiles of Klebsiella pneumoniae carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the in vitro activity of polymyxin B and minocycline combination therapy against six KPC-2-producing K. pneumoniae isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing K. pneumoniae is dependent on polymyxin B susceptibility. Further in vitro and animal studies must be performed to fully evaluate the efficacy of this drug combination